U.S. patent application number 13/540355 was filed with the patent office on 2013-01-17 for drug elution medical device.
This patent application is currently assigned to Boston Scientific Scimed, Inc.. The applicant listed for this patent is Martyn FOLAN, Fergal HORGAN, Marie TURKINGTON. Invention is credited to Martyn FOLAN, Fergal HORGAN, Marie TURKINGTON.
Application Number | 20130018448 13/540355 |
Document ID | / |
Family ID | 46548836 |
Filed Date | 2013-01-17 |
United States Patent
Application |
20130018448 |
Kind Code |
A1 |
FOLAN; Martyn ; et
al. |
January 17, 2013 |
DRUG ELUTION MEDICAL DEVICE
Abstract
An endoprosthesis (e.g., a sleeve) can be used to deliver
therapeutic agents to lesion sites. In some embodiments, one or
more sleeves can be delivered to one or more body lumen sites in
relatively few intervention procedures. The sleeve can be used to
deliver therapeutic agents to a de novo site or the site of a
previously deployed stent, or a stent may be co-administered along
with one or more sleeves.
Inventors: |
FOLAN; Martyn; (Co. Galway,
IE) ; HORGAN; Fergal; (Co. Mayo, IE) ;
TURKINGTON; Marie; (Co. Mayo, IE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
FOLAN; Martyn
HORGAN; Fergal
TURKINGTON; Marie |
Co. Galway
Co. Mayo
Co. Mayo |
|
IE
IE
IE |
|
|
Assignee: |
Boston Scientific Scimed,
Inc.
Maple Grove
MN
|
Family ID: |
46548836 |
Appl. No.: |
13/540355 |
Filed: |
July 2, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61506811 |
Jul 12, 2011 |
|
|
|
Current U.S.
Class: |
623/1.11 ;
156/242; 623/1.27 |
Current CPC
Class: |
A61L 31/16 20130101;
A61F 2002/826 20130101; A61M 2025/1081 20130101; A61F 2/06
20130101; A61M 2025/1075 20130101; A61F 2/958 20130101; A61F
2250/0067 20130101; A61F 2210/0004 20130101; A61L 31/06 20130101;
A61M 2025/105 20130101; A61F 2002/0086 20130101 |
Class at
Publication: |
623/1.11 ;
623/1.27; 156/242 |
International
Class: |
A61F 2/06 20060101
A61F002/06; B32B 37/02 20060101 B32B037/02; A61F 2/84 20060101
A61F002/84 |
Claims
1. A medical device, comprising: a tubular assembly comprising a
first inner sleeve and a second outer sleeve overlying the first
inner sleeve, and a first release region disposed between the first
and second sleeves; the first and second sleeves each comprising: a
substrate layer having an adluminal surface and an abluminal
surface, the substrate layer comprising a matrix and a biologically
active agent; and a tissue-adhesive region disposed on the
abluminal surface.
2. The medical device of claim 1, wherein the matrix comprises a
polymer.
3. The medical device of claim 1, wherein one or both sleeve are
biodegradable within a period of about 1 month to about 3
months.
4. The medical device of claim 2, wherein the polymer is selected
from the group consisting of polyurethane, polyethylene, polylactic
acid, polyglycolic acid, polylactic-co-glycolic acid,
poly-DL-lactide, and any combination thereof.
5. The medical device of claim 1, wherein the tissue-adhesive
region is configured on the abluminal surface as a plurality of
strips, a plurality of dots, a continuous layer, a matrix mesh, a
plurality of longitudinal strips, a plurality of circumferential
strips, or any combination thereof.
6. The medical device of claim 5, wherein the tissue-adhesive
region comprises a repeating pattern of strips, dots, or both.
7. The medical device of claim 1, wherein the tubular assembly is
disposed on an abluminal surface of an expandable balloon.
8. The medical device of claim 7, wherein a second release region
is disposed between the first inner sleeve and the abluminal
surface of the expandable balloon.
9. The medical device of claim 1, wherein the first release region
is adherent to the adluminal surface of the substrate layer of the
second outer sleeve.
10. The medical device of claim 8, wherein the second release
region is adherent to an abluminal surface of an expandable
balloon.
11. The medical device of claim 1, wherein the tissue-adhesive
region comprises polyethylene glycol, dextran aldehyde, amino
acid-based adhesives, adhesive surface proteins, microbial surface
components-recognizing adhesive matrix molecules, fatty ester
modified PLA, fatty ester modified PLGA, gel particles,
poly(N-isopropylacrylamide) gel particles, or any combination
thereof.
12. The medical device of claim 1, wherein the release region
comprises contrast agents, proteins, synthetic glues, or any
combination thereof.
13. The medical device of claim 1, wherein the biologically active
agent is selected from the group consisting of paclitaxel,
everolimus, sirolimus, zotarolimus, and biolimus A9, and any
combination thereof.
14. The medical device of claim 1, further comprising one or more
additional sleeve overlying the second sleeve.
15. The medical device of claim 1, wherein the substrate layers in
the first and second sleeves comprise the same or different
material.
16. The medical device of claim 1, wherein the medical device
comprises a vascular cuff.
17. A method of treatment, comprising: (a) inserting the medical
device of claim 1 into a body lumen; (b) expanding the medical
device to adhere the second sleeve to a first portion of the body
lumen, wherein the first release region elutes within the body
lumen after (b); and (c) re-expanding the medical device to adhere
the first sleeve to a second portion of the body lumen, wherein the
medical device is disposed over an expandable balloon, and a second
release region disposed between the first sleeve and the expandable
balloon degrades into the body lumen after step (c).
18. The method of claim 17, wherein the body lumen comprises a
blood vessel or a bifurcated blood vessel or similar anatomical
architecture.
19. The method of claim 18, further comprising rapidly degrading a
body lumen adhered sleeve, comprising flushing a body lumen with
saline solution, changing a pH, administering cryo-treatment,
ultrasonicating, and combinations thereof.
20. A method of making a medical device, comprising: (a) applying a
solution comprising a polymer and biologically active agent to a
non-stick substrate to form a substrate layer; (b) applying
tissue-adhesive portions to the substrate layer to form a first
sleeve; (c) removing the first sleeve from the non-stick substrate;
and (d) disposing the first sleeve over an expandable balloon
coated with a first release agent.
21. A method according to claim 20, further comprising: (d)
applying a second release agent over the first sleeve.
22. A method according to claim 21, further comprising: (e)
applying a second solution comprising a second polymer and a second
biologically active agent to a non-stick substrate to form a second
substrate layer; (f) applying tissue-adhesive portions to the
second substrate layer to form a second sleeve; (g) removing the
second sleeve from non-stick substrate; and (h) disposing the
second sleeve over the second release agent-coated first sleeve to
provide a medical device comprising a tubular assembly.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority under 35 USC .sctn.119(e)
to U.S. Provisional Patent Application Ser. No. 61/506,811, filed
on Jul. 12, 2011, the entire contents of which are hereby
incorporated by reference.
TECHNICAL FIELD
[0002] This disclosure relates to medical devices for therapeutic
agent delivery, and more particularly, to medical devices
containing biodegradable polymer layers for therapeutic agent
delivery.
BACKGROUND
[0003] The body includes various passageways such as blood vessels
(e.g., arteries) and lumens. These passageways sometimes become
occluded (e.g., by a tumor or plaque). To widen an occluded vessel
or lumen, balloon catheters can be used, e.g., in angioplasty.
[0004] A balloon catheter can include an inflatable and deflatable
balloon carried by a long and narrow catheter body. The balloon can
be initially folded around the catheter body to reduce the radial
profile of the balloon catheter for easy insertion into the
body.
[0005] During use, the folded balloon can be delivered to a target
location in the vessel, e.g., a portion occluded by plaque, by
threading the balloon catheter over a guide wire placed in the
vessel. The balloon is then inflated, e.g., by introducing a fluid
into the interior of the balloon. Inflating the balloon can
radially expand the vessel so that the vessel can permit an
increased rate of blood flow. After use, the balloon is typically
deflated and withdrawn from the body.
SUMMARY
[0006] Therapeutic agents can be delivered to the vessels and
lumens of the body (body lumen) via medical devices, such as
endoprostheses. The present disclosure is based, at least in part,
on an endoprosthesis (e.g., a sleeve) that can be used to deliver
therapeutic agents to de novo lesion sites. In some embodiments,
one or more sleeves can be delivered to one or more body lumen
sites in relatively few intervention procedures. In some
embodiments, a sleeve can be used to deliver therapeutic agents to
the site of a previously deployed stent, or a stent may be
co-administered along with one or more sleeves (e.g., the sleeve
may be disposed on an abluminal surface of the stent, the adluminal
surface of the stent, or both).
[0007] Accordingly, in one aspect, the disclosure features a
medical device, including a tubular assembly that includes a first
inner sleeve and a second outer sleeve overlying the first inner
sleeve, and a first release region disposed between the first and
second sleeves. Each of the first and second sleeves includes a
substrate layer having an adluminal surface and an abluminal
surface, each layer includes a matrix (e.g., a matrix including a
polymer) and a biologically active agent; and a tissue-adhesive
region disposed on the abluminal surface.
[0008] In another aspect, this disclosure features a method of
treatment, including (a) inserting a medical device into a body
lumen; (b) expanding the medical device to adhere the second sleeve
to a first portion of the body lumen; and (c) re-expanding the
medical device to adhere the first sleeve to a second portion of
the body lumen. The medical device includes a tubular assembly
including a first inner sleeve and a second outer sleeve overlying
the first inner sleeve, and a first release region disposed between
the first and second sleeves. Each of the first and second sleeves
includes a substrate layer having an adluminal surface and an
abluminal surface, the layer includes a polymer and a biologically
active agent; and a tissue-adhesive region disposed on the
abluminal surface.
[0009] In yet another aspect, this disclosure features a method of
making a medical device, including (a) applying a solution
including a polymer and biologically active agent to a non-stick
substrate to form a substrate layer; (b) applying tissue-adhesive
portions to the substrate layer to form a first sleeve; (c)
removing the first sleeve from the non-stick substrate; and (d)
disposing the first sleeve over an expandable balloon, coated with
a first release agent.
[0010] Embodiments of the above-mentioned medical devices can have
one or more of the following features.
[0011] In some embodiments, one or more sleeve is biodegradable
within a period of about 1 month to about 3 months. The matrix
including a polymer can include any of the polymers described,
infra. For example, the polymer can be selected from the group
consisting of polyurethane, polyethylene, polylactic acid,
polyglycolic acid, polylactic-co-glycolic acid, poly-DL-lactide,
and any combination thereof.
[0012] The tissue-adhesive region can be configured on the
abluminal surface as a plurality of strips, a plurality of dots, a
continuous layer, a matrix mesh, a plurality of longitudinal
strips, a plurality of circumferential strips, or any combination
thereof. The tissue-adhesive region can include a repeating pattern
of strips, dots, or both. The tissue adhesive region can include
about 5 percent or more and/or about 95 percent or less of an
abluminal surface area of the substrate layer of each sleeve. The
tissue-adhesive region can include any of the tissue adhesive
substances described, infra. For example, the tissue-adhesive
region can include polyethylene glycol, dextran aldehyde, amino
acid-based adhesives, adhesive surface proteins, microbial surface
components-recognizing adhesive matrix molecules ("MSCRAMMS"),
fatty ester modified PLA, fatty ester modified PLGA, gel particles,
poly(N-isopropylacrylamide) gel particles, or any combination
thereof.
[0013] The first release region can be adherent to the adluminal
surface of the substrate layer of the second outer sleeve. A second
release region can be disposed between the first inner sleeve and
the abluminal surface of the expandable balloon. The second release
region can be adherent to an abluminal surface of an expandable
balloon. The release region can include, for example, contrast
agents (e.g., iopromide), proteins (e.g., gelatin-based glues,
protein-based adhesives), synthetic glues (e.g., cyanoacrylates),
or any combination thereof.
[0014] The biologically active agent can include any of the
biological active agents described, infra. For example, the
biologically active agent can be selected from the group consisting
of paclitaxel, everolimus, sirolimus, zotarolimus, and biolimus A9,
and any combination thereof.
[0015] In some embodiments, the tubular assembly can be disposed on
an abluminal surface of an expandable balloon. The medical device
can further include one or more additional sleeve overlying the
second sleeve. The substrate layers in the first and second sleeves
can include the same or different material. In some embodiments,
the medical device can include a vascular cuff.
[0016] In some embodiments, for the method of treatment, the first
release region can elute within the body lumen after step (b). A
second release region between the first sleeve and the expandable
balloon can degrades into the body lumen after step (c). The method
of treatment can further include rapidly degrading a body lumen
adhered sleeve, such as by flushing a body lumen with saline
solution, changing a pH, administering cryo-treatment,
ultrasonicating, or combinations thereof. The medical device can be
disposed over an expandable balloon. The body lumen can include a
blood vessel or a bifurcated blood vessel or similar anatomical
architecture.
[0017] In some embodiments, the method of making a medical device
can further include (d) applying a second release agent over the
first sleeve, (e) applying a second solution comprising a second
polymer and a second biologically active agent to a non-stick
substrate to form a second substrate layer; (f) applying
tissue-adhesive portions to the second substrate layer to form a
second sleeve; (g) removing the second sleeve from non-stick
substrate; and/or (h) disposing the second sleeve over the second
release agent-coated first sleeve to provide a medical device
comprising a tubular assembly.
[0018] Embodiments of the above-mentioned medical devices can have
one or more of the following advantages.
[0019] In some embodiments, the medical device is capable of
delivering more than one drug. A plurality of devices can be
arranged for use in multiple target lesions during a given
intervention. The medical device can be relatively easily made by
spraying, and/or dipping. The medical device can be scaled for
peripheral or coronary interventions. For example, the medical
device can be larger for peripheral vessels. In some embodiments,
the medical device can be used for diffuse lesions, for bifurcated
vessels, and/or for use in medical procedures that require bailout.
In some embodiments, the medical device can be used without
tertiary equipment, thereby providing cost benefits. In some
embodiments, the medical device can minimize the overall clinical
procedural time while reducing the requirement for additional
interventional procedures. Examples of tertiary equipment and
additional interventions include stenting or scenarios where
multiple devices may be required for treatment of a vascular
lesion.
[0020] The medical devices of the present disclosure include
implantable and insertable medical devices that are used for the
treatment of various mammalian tissues and organs. As used herein,
"treatment" refers to the prevention of a disease or condition, the
reduction or elimination of symptoms associated with a disease or
condition, or the substantial or complete elimination of a disease
or condition. Subjects are vertebrate subjects, more typically
mammalian subjects including human subjects, pets and
livestock.
[0021] As used herein, a "layer" of a given material is a region of
that material whose thickness is substantially less than its length
and width. Layers can be in the form of open structures (e.g.,
sheets, in which case the thickness of the layer is substantially
less than the length and width of the layer), and partially closed
structures (e.g., open tubes, in which case the thickness of the
layer is substantially less than the length and diameter of
tube).
[0022] As used herein, a polymer is "biodegradable" if it undergoes
bond cleavage along the polymer backbone in vivo, regardless of the
mechanism of bond cleavage (e.g., enzymatic breakdown, hydrolysis,
oxidation, etc.). A biodegradable polymer includes "bioerosion" or
"bioabsorption" of a polymer-containing component of a medical
device (e.g., a polymer-containing layer), as well as other in vivo
disintegration processes such as dissolution, etc. Biodegradability
is characterized by a substantial loss in vivo over time (e.g., the
period that the device is designed to reside in a patient) of the
original polymer mass of the component. For example, losses may
range from 50% to 75% (e.g., to 90%, to 95%, to 97%, to 99%, or
more) of the original polymer mass of the device component.
Bioabsorption times may vary widely, for example, bioabsorption
times can range from several hours to approximately one year.
[0023] The details of one or more embodiments of the disclosure are
set forth in the accompanying drawings and the description below.
Other features, objects, and advantages of the disclosure will be
apparent from the description and drawings, and from the
claims.
DESCRIPTION OF DRAWINGS
[0024] FIG. 1A is a side view of an embodiment of a medical
device;
[0025] FIG. 1B is a cross-sectional view of an embodiment of a
medical device;
[0026] FIG. 1C is an enlarged cross-sectional view of an embodiment
of a medical device;
[0027] FIGS. 2A-2C are side views of an embodiment of a medical
device during deployment;
[0028] FIGS. 3A-3C are cross-sectional views of an embodiment of a
medical device in a body lumen;
[0029] FIGS. 4A-4C are cross-sectional views of an embodiment of a
medical device in a body lumen;
[0030] FIGS. 5A-5B are cross-sectional views of an embodiment of a
medical device;
[0031] FIGS. 6A-6C are enlarged cross-sectional views of an
embodiment of a medical device during deployment;
[0032] FIGS. 7A-7C are side views of an embodiment of a medical
device during deployment;
[0033] FIGS. 8A-8B are side views of an embodiment of a medical
device during deployment;
[0034] FIGS. 9A-9C show an embodiment of a method of manufacture of
a medical device; and
[0035] FIGS. 10A-10C show an embodiment of a method of manufacture
of a medical device.
[0036] Like reference symbols in the various drawings indicate like
elements.
DETAILED DESCRIPTION
[0037] In embodiments, this disclosure relates to a medical device
(e.g., a vascular cuff or a sleeve) that can elute a therapeutic
agent. The medical device can provide improved single or multiple
delivery of a therapeutic agent to, for example, peripheral and/or
cardiovascular body lumen walls. The medical device can be carried
by an inflatable carrier balloon. When the balloon is inflated in a
vascular lumen, the medical device can intimately contact the
vasculature and adhere to the interior of a lumen's treatment site
(e.g., endothelial cells lining the vasculature, atherosclerotic
plaque at a targeted site). Upon subsequent balloon deflation and
withdrawal, the vascular cuff remains at the treatment site.
[0038] The medical device (e.g., a sleeve) can provide drug
delivery in a temporary capacity. For example, when a sleeve is
degradable, the sleeve can decrease the likelihood of
device-related thrombosis or embolism while providing drug
treatment for vascular inflammation, and delayed
re-endothelialization. In some embodiments, the sleeve can be used
to treat sites where stent implantation is not desirable, such as
small vessels, bifurcated lumen treatment sites, in-stent
restenosis, and acute ST-elevation myocardial infarction. The
sleeve can be used for de novo vascular lesions, where an unstented
body lumen wall has lesions, calcified or otherwise. The sleeve can
be used for secondary treatment at locations where restenosis has
formed. The sleeve can be used instead of or in addition to
drug-eluting stents. In some embodiments, the sleeve can
homogenously deliver therapeutic agents (e.g., an anti-restenotic
agent such as paclitaxel, everolimus, rapamycin, biolimus,
zotarolimus, etc.) to a target lesion, which can decrease the
likelihood of vascular stiffening, while maintaining the
accessibility of the blood vessel to re-intervention and decreasing
the likelihood of restenosis, when compared to conventional
interventions (e.g., stent implantation, balloon angioplasty).
[0039] Referring to FIG. 1A, the medical device can have a tubular
construction, in the form of a sleeve 100 (e.g., a vascular cuff).
Sleeve 100 can be used in conjunction with a carrier balloon
expandable catheter 102 and can be left within a blood vessel
following balloon deployment and withdrawal. The sleeve can deliver
therapeutic agents during or in addition to angioplasty procedures,
and can provide prolonged drug delivery to a body lumen wall after
angioplasty procedures. In some embodiments, the sleeve can provide
one or more therapeutic agents, which can elute over specific time
frames and/or in particular sequences. The sleeve can decrease the
likelihood of drug loss from a body lumen wall, or the premature
drug loss from a drug delivery device, for example, when a drug
delivery device is maneuvered through a blood vessel.
[0040] Referring to FIGS. 1B and 1C, a sleeve 100 can include a
biodegradable substrate layer 104 and one or more tissue adhesive
region(s) 106 on an abluminal surface of the sleeve. One or more
balloon release region(s) 108 can be disposed on an adluminal
surface of the sleeve, between sleeve 100 and balloon 102.
Biodegradable substrate 104 can provide structural shape to the
sleeve, and a matrix 110 (e.g., a polymeric matrix) which can
contain a therapeutic agent 112. Biodegradable substrate layer 104
can protect the therapeutic agent, for example, until a target
treatment site is reached. The polymer matrix 110 can elute the
therapeutic agent in a controlled manner. After drug elution is
completed during a predetermined time frame, biodegradable
substrate layer 104 can degrade in a controlled manner leaving
little or no residual components at the treatment site.
[0041] In some embodiments, referring to FIGS. 2A-2C, a sleeve 100
can be administered using a balloon carrier 102 in a target area
101 of a body lumen. The balloon can be inserted into a target area
(FIG. 1A), inflated to adhere the sleeve to the target area (FIG.
1B), then deflated and withdrawn from the target area (FIG. 1C)
while leaving the sleeve in the body lumen. In some embodiments,
when implanted in a body lumen, the sleeve is biodegradable within
a period of two weeks or more (e.g., one month or more, six weeks
or more, or two months, or more) to three months or less (e.g., two
months or less, six weeks or less, or one month, or less). In some
embodiments, the sleeve can degrade within a period of about
several minutes or more (e.g., about two minutes or more, about
five minutes or more, about ten minutes or more, about 20 minutes
or more, about an hour or more, about five hours or more, about 12
hours or more, or about 24 hours, or more). The biodegradability of
the sleeve can depend on the polymers of the biodegradable
substrate layer, the tissue adhesive region, and the therapeutic
agent.
[0042] For example, in a sleeve including PLGA, the copolymer ratio
of lactide to glycolide can determine the rate of polymer
degradation, where the higher the lactide content, the slower the
degradation. In some embodiments, molecular weight can affect the
degradation, where the lower the molecular weight, the faster the
degradation (when the molecular weight is below the range where
T.sub.g is affected). In some embodiments, a polymer end group can
be used to control the rate of degradation. For example, an alkyl
end group associated with a co-polymer, such as PDLLA, can result
in slower degradation than a polymer with an acid end group, such
as in PLGA. In some embodiments, factors such as crystallinity,
drug percent loading, and/or other additives can also affect
degradation. For example, the addition of a therapeutic agent such
as a hydrophobic drug (e.g., everolimus or paclitaxel) can be used
to delay the rate of molecular weight loss.
[0043] In some embodiments, for thicknesses of less than or equal
to about 200 .mu.m, sleeve thickness can have minimal impact on
degradation. In some embodiments, for thicknesses of greater than
about 200 .mu.m, oligomers diffuse out of a polymer layer at a
relatively slow rate, resulting in an accumulation of acidic
molecular weight degradation products at the center of the
material, which can cause autocatalytic degradation (e.g.
heterogeneous degradation). As an example, in vitro mass loss in
bio-relevant media at 37.degree. for a film of about 200 .mu.m
thick including 85/15 lactide:glycolide PLGA co-polymer can
demonstrate greater than 85% mass loss in less than about 180
days.
[0044] Matrix materials which may be used to form biodegradable
substrate layers include synthetic and natural biodegradable
polymers. Synthetic biodegradable polymers include polyesters, for
example, selected from homopolymers and copolymers of lactide,
glycolide, and epsilon-caprolactone, including poly(L-lactide),
poly(D, L-lactide), poly(lactide-co-glycolides) such as
poly(L-lactide-co-glycolide) and poly(D, L-lactide-co-glycolide),
polycarbonates including trimethylene carbonate (and its alkyl
derivatives), polyphosphazines, polyanhydrides, polyorthoesters,
and biodegradable polyurethanes. Natural biodegradable polymers
include proteins, for example, selected from fibrin, fibrinogen,
collagen and elastin, and polysaccharides, for example, selected
from chitosan, gelatin, starch, and glycosaminoglycans such as
chondroitin sulfate, dermatan sulfate, keratin sulfate, heparin,
heparan sulfate, and hyaluronic acid. In some embodiments, the
polymers can include one or more of alginate, dextran, chitin,
cotton, polylactic acid-polyethylene oxide copolymers, cellulose,
and chitins. Blends of the above natural and synthetic polymers may
also be employed.
[0045] In some embodiments, polymers suitable for biodegradable
substrate layers can include without limitation polyurethane and
its copolymers, silicone and its copolymers, ethylene
vinyl-acetate, polyethylene terephthalate, thermoplastic
elastomers, polyvinyl chloride, polyolefins, cellulosics,
polyamides, polyesters, polysulfones, polytetrafluorethylenes,
polycarbonates, acrylonitrile butadiene styrene copolymers,
acrylics, polycarbonate, poly(glycolide-lactide) copolymer,
Tecothane, PEBAX, polyethylene, polylactic acid,
poly(.gamma.-caprolactone), poly(.gamma.-hydroxybutyrate),
polydioxanone, poly(.gamma.-ethyl glutamate), polyiminocarbonates,
poly(ortho ester), and/or polyanhydrides. Additional polymeric
materials are described, for example, in U.S. Pat. Nos. 5,650,234
and 5,463,010, herein incorporated in their entirety. Blends of the
above polymers may also be employed.
[0046] In some embodiments, biodegradable substrate layer 104
includes biodegradable materials, such as polyglycolic acid,
polylactic acid, poly(lactic-co-glycolic acid), poly-DL-lactide,
and/or other known degradable polymers. Biodegradable substrate
layer 104 can also include non-biodegradable materials, such as
Tecothane, PEBAX, and/or polyethylene. In some embodiments,
biodegradable substrate layer 104 contains, for example, from 1 to
100 wt % (e.g., from about 25 to about 50 wt %, from about 25 to
about 75 wt %, from about 75 to about 90 wt %, from about 85 to
about 99 wt %, from about 90 to about 99 wt %, from about 95 to
about 99 wt %, 100 wt %) of one or more biodegradable polymers. In
some embodiments, the weight percent of biodegradable material can
be about 80% or more (e.g., about 90% or more, about 95% or more,
or about 99% or more) of the total polymer contained by
biodegradable substrate layer 104. The weight percent of
non-biodegradable material can be about 20% or less (e.g., about
10% or less, about 5% or less, or about 1% or less) of the total
polymer contained by biodegradable substrate layer 104. In some
embodiments, incorporation of a non-biodegradable material can
provide increased stability to the resulting material, such that
the biodegradable substrate layer can have increased resistance to
degradation (e.g., during storage, in humid environments). In some
embodiments, biodegradable substrate layer 104 can be in the form
of a fibrous scaffold with an open porous structure that encourages
three-dimensional migration and proliferation of cells within the
fibrous scaffold. Examples of biodegradable substrate layer 104
include non-porous layers and porous layers.
[0047] Biodegradable substrate layer 104 can have any dimension
that functions as described herein. For example, in some
embodiments, biodegradable substrate layer 104 can have a thickness
of about 5 nm or more (e.g., about 10 nm or more, about 20 nm or
more, about 50 nm or more, about 100 nm or more, about 500 nm or
more, about one micron or more, about 10 microns or more, about 25
microns or more, about 50 microns or more, or about 70 microns or
more) and/or about 80 .mu.m or less (about 70 microns or less,
about 50 microns or less, about 25 microns or less, about 10
microns or less, about one micron or less, about 500 nm or less,
about 100 nm or less, about 50 nm or less, about 20 nm or less, or
about 10 nm or less). In some embodiments, biodegradable substrate
layer 104 can be a uniform layer or patches that may or may not be
interconnected. The biodegradable substrate layer can define the
length and expanded diameter of the sleeve. For example, the
biodegradable substrate layer can have a length of about four mm or
more (e.g., about ten mm or more, about 20 mm or more, about 30 mm
or more, about 40 mm or more, or about 50 mm or more) and/or about
60 mm or less (e.g., about 50 mm or less, about 40 mm or less,
about 30 mm or less, about 20 mm or less, or about ten mm or
less).). In some embodiments, the biodegradable substrate layer can
have an expanded diameter of about 2 mm or more (e.g., about 3 mm
or more, about 4 mm or more, or about 5 mm or more) and/or about 6
mm or less (e.g., about 5 mm or less, about 4 mm or less, or about
3 mm or less).
[0048] In some embodiments, tissue-adhesive region 106 can include
one or more tissue-adhesive substances. The tissue-adhesive
substances can be provided in biodegradable substrate layer 104
(e.g., evenly dispersed in the layer or having a higher
concentration at a tissue contacting surface of the layer). In some
embodiments, one or more adhesive substances can be provided in an
adhesive region that is disposed over the surface of biodegradable
substrate layer 104 (which adhesive region may penetrate the
biodegradable substrate layer to a certain degree). For example, a
pure layer of an adhesive substance or a layer containing an
adhesive substance and a suitable excipient may be applied to a
tissue contacting surface of a biodegradable substrate layer. The
tissue-adhesive region allows the sleeve to be in close proximity
to the vasculature, reducing the potential for blood leakage from
the sleeve into the body lumen while providing therapeutic agent
delivery to a vascular treatment site.
[0049] In some embodiments, the tissue-adhesive region can be
configured as a plurality of strips, a plurality of dots, a
continuous layer, a matrix mesh, a plurality of longitudinal
strips, a plurality of circumferential strips, or any combination
thereof. The tissue-adhesive region can include a repeating pattern
of dots and/or strips at predetermined locations. In some
embodiments, the tissue adhesive region is disposed over about 5%
or more (e.g., about 10% or more, about 15% or more, about 20% or
more, about 25% or more, about 30% or more, about 50% or more,
about 75% or more, or about 90% or more) and/or about 95% or less
(about 90% or less, about 75% or less, about 50% or less, about 30%
or less, about 25% or less, about 20% or less, about 15% or less,
or about 10% or less) of the abluminal surface area of the
biodegradable substrate layer that the tissue-adhesive region is
disposed on. In some embodiments, the tissue adhesive region can
cover greater than 0% up to 100% of the surface area of an
immediately underlying biodegradable substrate layer. The tissue
adhesive region can be porous. In some embodiments, when the tissue
adhesive region covers 100% of the underlying biodegradable
substrate layer, the adhesive region can protect a therapeutic
agent until a treatment site is reached. The surface area of the
tissue adhesive region can be dependent on the adhesive properties.
In some embodiments, the tissue adhesive region does not delay drug
elution from the sleeve.
[0050] In some embodiments, the tissue-adhesive region can have a
thickness of about ten nm or more (e.g., about 20 nm or more, about
30 nm or more, about 40 nm or more, about 50 nm or more, about 60
nm or more, about 70 nm or more, about 80 nm or more, or about 90
nm or more) and/or about 100 nm or less (about 90 nm or less, about
80 nm or less, about 70 nm or less, about 60 nm or less, about 50
nm or less, about 40 nm or less, about 30 nm or less, or about 20
nm or less). In some embodiments, the tissue-adhesive region
thickness can be influenced by the choice of adhesive. For example,
a protein-based adhesive layer can be in the form of a chain of
amino acids (a thickness of less than about 10 nm) or can have a
thickness that is as large as the sub-micron based
poly(N-isopropylacrylamide) gel particles.
[0051] A tissue adherent strength of a material can be assessed
through in vitro based peel tests and nano-indentation, typically
used to measure the interfacial adhesive properties. For example,
nano-indentation data (indicative of Youngs modulus, hardness) can
be used to correlate thickness with adhesive properties. In some
embodiments, the lap-shear strength of a given adhesive can be
evaluated to comply with values reported for typical soft-tissue
adhesives (about 15 to about 45 kPa).
[0052] Tissue-adhesive region can include bioadhesive materials,
such as natural polymeric materials, synthetic materials, and
synthetic materials formed from biological monomers such as sugars.
Tissue adhesives can also be obtained from the secretions of
microbes, marine mollusks, and crustaceans. The tissue adhesives
can have better adhesion to body tissue, and can have better
adhesion to the abluminal surface of a sleeve that the adhesive is
attached to rather than to the adluminal surface of an overlying
sleeve, or to an overlying release region. In other words, the
adhesion at the interface of the sleeve and the carrier balloon (or
at the interface of the sleeve and an adjacent stacked sleeve) is
weaker than the adhesion at the interface of the biodegradable
substrate layer and the tissue adhesive disposed thereon (or at the
interface of the tissue adhesive and the body tissue) so that the
biodegradable substrate layer remains with the tissue adhesive
region when the carrier balloon is retracted from the body.
[0053] In some embodiments, the tissue-adhesive region includes an
adhesive material such as polyethylene glycol, dextran aldehyde,
amino acid-based adhesives, adhesive surface proteins, microbial
surface components recognizing adhesive matrix molecules
("MSCRAMMs"), fatty ester modified PLA, fatty ester modified PLGA,
gel particles, and/or poly(N-isopropylacrylamide) gel
particles.
[0054] As an example, a polar molecule may be employed as an
adhesive material for the adhesive region. Examples of such polar
molecules include poly(amino acids). For instance, in some
embodiments, an amphipathic poly(amino acid) is used as an adhesive
material. The amphipathic poly(amino acid) may have a hydrophobic
poly(amino acid) tail (e.g., ranging from 2 to 400 or more amino
acids in length) to encourage interaction with the lesion. Examples
of hydrophobic amino acids include phenylalanine, leucine,
isoleucine and valine, among others. The amphipathic poly(amino
acid) may have a hydrophilic poly(amino acid) head (e.g., ranging
from 2 to 400 or more amino acids in length) to encourage
interaction with the biodegradable polymer (where a hydrophilic
polymer such as hyaluronic acid is employed). Examples of
hydrophilic amino acids include basic amino acids (e.g., lysine,
arginine, histidine, ornithine, etc.), acidic amino acids (e.g.,
glutamic acid, aspartic acid, etc.), and neutral amino acids (e.g.,
cysteine, asparagine, glutamine, serine, threonine, tyrosine,
glycine). The hydrophilic poly(amino acid) head can be zwitterionic
to promote ion-dipole bonding with the biodegradable polymer (where
a hydrophilic polymer such as hyaluronic acid is employed). Such a
polymer head can contain a mixture of acidic (anionic) and basic
(cationic) amino acids and may range, for example, from 2 to 400 or
more amino acids in length.
[0055] A poly(amino acid) containing a cell-binding peptide such as
YIGSR or RGD can be employed as an adhesive material for the
adhesive region. Such sequences can be repeated if desired. The
poly(amino acid) may further comprise a hydrophilic poly(amino
acid) chain (e.g., typically ranging from about 2 to about 400 or
more amino acids in length) to promote interaction with the
biodegradable polymer (where a hydrophilic polymer such as
hyaluronic acid is employed).
[0056] In some embodiments, the amino acid 3,4-dihydroxyphenyl
alanine (DOPA) or a poly(amino acid) chain that includes multiple
DOPA units can be used as an adhesive substance for the adhesive
region. Such chains may further include lysine units, along with
the DOPA units. See Statz et al. J. Am. Chem. Soc. 127, 2005,
7972-7973, wherein a 5-mer anchoring peptide
(DOPA-Lys-DOPA-LysDOPA) was chosen to mimic the DOPA- and Lys-rich
sequence of a known mussel adhesive protein.
[0057] In some embodiments, MSCRAMMs (microbial surface components
recognizing adhesive matrix molecules) are employed as adhesive
substances. Examples of MSCRAMMs include fibronectin binding
proteins (e.g., FnBPA, FnBPB, etc.) and fibrinogen binding proteins
(e.g., C1fA, C1fB, etc.), among others. See, e.g., Timothy Foster,
Chapter 1, "Surface protein adhesins of staphylococci," from
Bacterial Adhesion to Host Tissues: Mechanisms and Consequences,
Edited by Michael Wilson, 2002, pages 3-11.
[0058] In some embodiments, because plaque lesions are known to be
hydrophobic, a hydrophobic drug (e.g., paclitaxel, among many
others) can be provided over or within the biodegradable polymer
containing layer, encouraging adhesion and/or uptake by the lesion
upon contact with a lesion.
[0059] Referring to FIGS. 2A-2C, tissue adhesive region 106 can
cause an interference fit (e.g., a mechanical interaction) between
the sleeve 100 and an inner surface 114 of the vascular wall to
which it contacts, thereby retaining the sleeve at the target area.
Referring to FIGS. 3A-3C, tissue adhesive region 106 can improve
the therapeutic agent's local proximity, and/or reduce a required
dosage of a therapeutic agent to the target treatment area's
cellular lining 114, for example, by decreasing therapeutic agent
wash-off to the body lumen. In some embodiments, therapeutic agent
112 can diffuse out of the sleeve to be absorbed by a vessel wall
and the diffusion rate can be controlled by a therapeutic agent
concentration within the sleeve and the substrate properties. For
example, the ratio of polymer to therapeutic agent can influence
the porosity of the sleeve and affect the ability of the
therapeutic agent to diffuse out of the matrix. A greater ratio of
therapeutic agent can increase the porosity of the sleeve and
increase therapeutic agent diffusion. Thus, the therapeutic agent
can elute into a blood vessel wall after implantation of the sleeve
over a predetermined duration. Once the drug has finished eluting,
the sleeve can degrade to reduce the likelihood of adverse
biological reactions (e.g., embolic formation) and to return a
vascular lining to its native condition. In some embodiments,
referring to FIG. 3C, tissue adhesive region 106 can remain within
the body lumen after the clinical procedure is completed. In some
embodiments, tissue adhesive region 106 can substantially degrade
(e.g., degrade by about 80 wt % or more, degrade by about 90 wt %
or more, degrade by about 95 wt % or more) before the complete
degradation of layer 104, or can substantially degrade after layer
104 has completely degraded.
[0060] In some embodiments, tissue adhesive region 106 can include
hydrogels (e.g., polyethylene glycol:dextran aldehyde) to allow for
a strong attractive force to the inner surface of a blood vessel.
In some embodiments, referring to FIGS. 4A-4C, the attractive force
between tissue adhesive region 106 and a lumen wall tissue is
greater than the retention force between the adluminal surface of
the sleeve and the balloon's outer surface, such that the dilation
and pressurization of tissue-adhesive region 106 to lumen's inner
surface (e.g., endothelial cell layer, a vascular plaque) sever the
retention force between sleeve 100 and balloon 102. Subsequent to
balloon deflation and withdrawal, the tissue-adhesive region 106
retains the vascular cuff in intimate contact with the vasculature.
The retention force between sleeve 100 and balloon 102 can result
from chemical adhesive forces (e.g., exerted by release region 108)
or physical forces (e.g., frictional forces between sleeve 100 and
carrier balloon 102).
[0061] Referring back to FIG. 1C, balloon 102 can be coated in part
or in full with one or more balloon release region(s) 108. Balloon
release region 108 can help retain sleeve 100 on balloon 102, which
is loaded onto the balloon catheter. Balloon release region can be
temporary and biocompatible. For example, balloon release region
108 can include formulations of a contrast agent, such as iopromide
(Ultravist.RTM.), which can be used as a contrast medium and as
balloon adhesive. In some embodiments, the release region can be
configured as a plurality of strips, a plurality of dots, a
continuous layer, matrix mesh, a plurality of longitudinal strips,
a plurality of circumferential strips, or any combination thereof.
The release region can include a repeating pattern of dots and/or
strips, which can be at predetermined locations. In some
embodiments, the release region are disposed over about 5% or more
(e.g., about 10% or more, about 15% or more, about 20% or more,
about 25% or more, about 30% or more, about 50% or more, about 75%
or more, or about 90% or more) and about 95% or less (e.g., about
90% or less, about 75% or less, about 50% or less, about 30% or
less, about 25% or less, about 20% or less, about 15% or less, or
about 10% or less) of the abluminal surface area of an underlying
balloon or sleeve. In some embodiments, the release region can
cover greater than 0% up to 100% of the surface area of an
underlying balloon or sleeve. The release region can be porous. The
surface area of the release region can be dependent on its adhesive
and degradation properties. As an example, in some embodiments,
specimens including a total surface area of about 0.4 cm.sup.2 of a
gelatin-based biomimetic adhesive can generate adhesive strengths
of 12-23 kPa. Therefore, the adhesive strength can be appropriately
adjusted by modulating the extent of the contact surface area.
[0062] In some embodiments, the release region can have a thickness
of about ten nm or more (e.g., about 20 nm or more, about 30 nm or
more, about 40 nm or more, about 50 nm or more, about 60 nm or
more, about 70 nm or more, about 80 nm or more, or about 90 nm or
more) and/or about 100 nm or less (about 90 nm or less, about 80 nm
or less, about 70 nm or less, about 60 nm or less, about 50 nm or
less, about 40 nm or less, about 30 nm or less, or about 20 nm or
less).
[0063] In some embodiments, the release region can include contrast
agents (e.g., iopromide), proteins (e.g., gelatin-based glues,
protein-based adhesives), synthetic glues (e.g., cyanoacrylates),
or any combination thereof. For example, the release region can
include gelatin-based glues (e.g., resorbable biological glues such
as GRFG--gelatin, resorcinol, formaldehyde, glutaraldehyde),
gelatin hydrogel glues, cyanoacrylates (e.g. Histoacryl blue),
adhesive based on protein engineering (e.g., high grade
bio-compatibility and biodegradability internal adhesives). In some
embodiments, for better retention of the release region on a
balloon surface or on an underlying sleeve surface during delivery,
the release region can include crosslinked gel particles, or the
gel particles can be mixed with a higher molecular weight
polymer.
[0064] In some embodiments, the balloon surface can have "windows"
that can allow for release of a physico-mechanical signal across
the "window" to facilitate sleeve detachment. A "window" can
include a hole, aperture, a pore, a thinner area of the same
polymer, and/or a membrane of an alternate material. For example,
the windows can enable the transfer of a detachment agent (e.g., a
change in temperature, a change in pH) across the window when the
deployment balloon has been flushed with an appropriate catalyst.
The catalyst can include an external agent, which can be physical
or chemical in nature. As an example, a cryo-technique such as that
used in the cryo-catheter devices can deliver extreme cold (a
catalyst) from the tip of an ablation catheter or through a
balloon. Similarly, heat (a catalyst) can be applied in this
manner. In some embodiments, adhesion can be regulated through
modulation of pH. For example, the availability of local calcium
ions (a catalyst) can be adjusted and used to vary alkaline
balance.
[0065] The catalyst can initiate localized site degradation of a
window, when the window is, for example, a thinner area of the same
polymer or of a membrane of an alternate material. In some
embodiments, the catalyst can initiate the degradation of a balloon
adhesive to allow a sleeve to be detached and deployed at a
treatment site. The catalyst can be released through, for example,
a hole, an aperture, a pore, a thinner area of the same polymer, or
a membrane of an alternate material.
[0066] In some embodiments, multiple sleeves are arranged in a
stacked configuration, where a relatively outer sleeve
circumferentially overlies a relatively inner sleeve. When arranged
in a stacked configuration, multiple sleeves can be delivered to
multiple lumen locations during a given intervention. In some
embodiments, referring to FIGS. 5A-5B, multiple sleeves are
arranged in a stacked configuration. Referring to FIG. 5B, an outer
sleeve 200 can have a biodegradable substrate layer 204 and
abluminal tissue-adhesive region 206. The outer sleeve 200 overlies
an inner sleeve 300, which in turn can have a biodegradable
substrate layer 304 and abluminal-tissue adhesive region 306.
Inter-sleeve release region 250 can exist between outer sleeve 200
and inner sleeve 300. A balloon-release region 350 can exist
between an innermost sleeve (e.g., sleeve 300) and a carrier
balloon 202. In some embodiments, the attractive force between
adhesive region 206 and a lumen's inner surface (e.g., adluminal
surface) is greater than the retention force between outer sleeve
200 and inner sleeve 300; and the adhesive force between the tissue
adhesive region 306 and a lumen's inner surface is greater than the
retention force between the innermost sleeve and the carrier
balloon. The retention force between outer sleeve 200 and inner
sleeve 300 can include chemical adhesive forces (e.g., exerted by
layer 250) or physical forces (e.g., frictional forces between
sleeves 200 and 300). Similarly, the retention force between inner
sleeve 300 and balloon 202 can result from chemical adhesive forces
(e.g., exerted by layer 350) or physical forces (e.g., frictional
forces between sleeve 300 and carrier balloon 202).
[0067] Referring to FIGS. 6A-6C, during deployment, first outer
sleeve 200 can be applied to a treatment site upon balloon
expansion. The balloon can then be deflated and advanced to a
second treatment site, where a second inner sleeve 300 can be
applied to a second treatment site upon balloon expansion. Stacked
configurations having greater than two sleeves can be delivered to
multiple treatment sites in an analogous manner. The stacked
sleeves can be delivered in a controlled manner to sequential
portions of the vasculature in a minimum amount of intervention
procedures (e.g., a single intervention). A stacked sleeve
configuration can be advantageous for diffuse lesion treatment,
where a treatment area is not well defined. In some embodiments, a
stacked configuration can be used for tapered body lumens, where
multiple sleeves can be placed within the body lumen with minimal
re-intervention (e.g., no re-intervention).
[0068] The stacked sleeves can each have different compositions.
For example, depending on the composition of the biodegradable
substrate layer, the tissue-adhesive region, and the therapeutic
agent carried by each of the sleeves, the sleeves can degrade at
different durations and can delivery different therapeutic agents
to various wall regions of a body lumen. In some embodiments,
inter-sleeve release and/or balloon-release region can each include
one or more release substances. The release substances can be
provided in the biodegradable substrate layer (e.g., evenly
dispersed in the layer or more preferably having a higher
concentration at a delivery vehicle contacting surface of the
layer).
[0069] In some embodiments, one or more release substances can be
provided in a release region that is disposed between the surfaces
of the carrier balloon (or an underlying sleeve) and the
biodegradable substrate layer of a given sleeve (which release
region may penetrate the degradable substrate layer to a certain
degree). One example of a release substance is zwitterionic
phosphorylcholine and its derivatives. Phosphorylcholine is able to
form ionic-dipole bonds with various polar substances, including
biodegradable polymers such as hyaluronic acid and polar balloon
materials such as PEBAX. In this way phosphorylcholine may act to
bind the biodegradable polymer portion of the sleeve to the balloon
material. When desired, a wetting agent (e.g., saline or water) can
be employed to disrupt the ionic-dipole interactions holding the
sleeve on the balloon.
[0070] In some embodiments, the wetting agent is supplied by the
delivery vehicle (e.g., a delivery balloon). For instance, an
inflatable micro-porous or weeping balloon may be used to dilate
the vessel site and deliver a wetting agent which interacts with
the zwitterionic phosphorylcholine. As another example, saline
loaded microspheres may be provided between the biodegradable
polymer containing layer and the balloon, which burst and release
their contents upon balloon inflation.
[0071] Other zwitterionic materials may be employed as release
substances including zwitterionic peptides. For example, peptides
with both basic amino acids (e.g., lysine, arginine, ornithine,
etc.) and acidic amino acids (e.g., glutamic acid, aspartic acid,
etc.) will have zwitterionic character for providing ionic
ionic-dipole bonds with various polar substances (e.g., a
hydrophilic biodegradable polymer or a hydrophilic balloon
material). Chains of non-polar amino acid chains (e.g.,
phenylalanine, leucine, isoleucine, valine, etc.) may be attached
to zwitterionic chains for providing hydrophobic interactions with
various nonpolar substances (e.g., a hydrophobic balloon
material).
[0072] Shear sensitive adhesives constitute another class of
release substance that may be used between a balloon delivery
vehicle and a sleeve. The basic principle of these adhesives is
that the shearing force that is created between the inflating
balloon and the adhesive will break the bond and facilitate
release. An example of such an adhesive is a blend of
polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG), which
would provide a biocompatible layer which adheres the balloon to
the biodegradable substrate layer until the device is in place at
the delivery site. Balloon dilation may be used to disrupt the
adhesive bonds and the sleeve may thus be released from the
balloon. The weight ratio of PVP to PEG in such blends may vary
widely, for example, ranging from 1:99 to 10:90 to 25:75 to 50:50
to 75:25 to 90:10 to 95:5 to 99:1.
[0073] In some embodiments, a release region degrades within the
body lumen after implantation of an overlying sleeve. The release
region degradation can be rapid, such that it can be completed
before delivery of an underlying sleeve (e.g., when the release
region adheres to an underlying sleeve after implantation of an
overlying sleeve). In some embodiments, the release region can
remain attached to the adluminal surface of an implanted overlying
sleeve and can degrade with the overlying sleeve in a body
lumen.
[0074] Degradation of the release region can occur in a controlled
manner. For example, degradation of the release region can be
completed in about three months or less (e.g., about two months or
less, about one month or less, about two weeks or less, about one
week or less, about three days or less, about two days or less,
about one day or less, about twelve hours or less, about six hours
or less, about one hour or less, about 30 minutes or less, about 15
minutes or less, about 5 minutes or less, or about one minute or
less) and/or about 30 seconds or more (e.g., about one minute or
more, about 5 minutes or more, about 15 minutes or more, about 30
minutes or more, about one hour or more, about six hours or more,
about twelve hours or more, about one day or more, about two days
or more, about three days or more, about one week or more, about
two weeks or more, about one month or more, or about two months or
more). This degradation profile can be designed to be of short
duration if a release region has already fulfilled its primary
function. In some embodiments, the release region degradation can
be matched to the duration of the sleeve degradation.
[0075] In some embodiments, when multiple sleeves are in a stacked
configuration, the stacked sleeves can be used for bi-furcated
treatment sites. Referring to FIG. 7A, a modeled bifurcated
vasculature with three associated lesions 420, 422, and 424 is
shown with two guidewire placement locations 430 and 432. Using
three stacked sleeves 400, 402, and 404, the three lesion sites can
be treated using a single interventional device as illustrated in
FIGS. 7B and 7C. With a guidewire at location 422, the most
proximal treatment site can be accessed and treated first with the
balloon to leave the outermost sleeve 402 at treatment site 422.
The balloon can now be advanced to the treatment site 420 and a
repeat inflation/deflation can be performed to leave the second
sleeve 400 at treatment site 422. Finally, the guide wire can be
partially withdrawn and replaced at guide wire position 424 with a
further inflation/deflation of the balloon to leave the innermost
sleeve 404 at site 424. After placement of the sleeves, the balloon
can be fully withdrawn. What remains after treatment (as shown in
FIG. 7C) are the three sleeves at the appropriate vascular
locations. The sleeves can deliver a predetermined therapeutic
agent and therapeutic agent dosage at each of the treatment
sites.
[0076] In some embodiments, the sleeve can also offer an
opportunity for bailout. For example, if unforeseen malposition or
vascular blockage is caused by a sleeve during use, the
introduction of an appropriate bolus of suitable fluid to the
locality of the problematic sleeve can be used to accelerate its
degradation and thus return a blood vessel to its unblocked state.
Treatment can be therefore administered without full interventional
procedures (e.g., surgical intervention). Without wishing to be
bound by theory, it is believed that malposition or vascular
blockage can have an increased risk of occurrence in procedures
involving distal vasculature with small lumen diameter. In some
embodiment, depending on the composition of the sleeve, accelerated
degradation of a sleeve can include flushing a body lumen with a
saline solution, changing the pH of the local environment of a
sleeve, administering cryo-treatment to the local environment of a
sleeve, and/or administering ultrasound to the local environment of
a sleeve. Accelerated degradation can occur over the period of
about one month or less (e.g., about three weeks or less, about two
weeks or less, about one week or less, about three days or less,
about one day or less, about 12 hours or less, about six hours or
less, about one hour or less, about 30 minutes or less, about 15
minutes or less, about five minutes or less, or about one minute or
less).
[0077] As an example, a sleeve can include a 200 .mu.m thick film
of about 85/15 lactide: glycolide PLGA co-polymer, and in vitro
mass loss tests can be conducted at 37.degree. C. in bio-relevant
media. Greater than 85% mass loss of the film can occur in less
than 180 days. As another example, a sleeve can include a 200 .mu.m
thick film of 50/50 lactide:glycolide PLGA co-polymer, and in vitro
mass loss studies can be conducted at 37.degree. C. in bio-relevant
media. Greater than 90% mass loss of the film can occur in less
than 145 days. Preclinical studies support these findings.
[0078] In some embodiments, referring to FIGS. 8A-8B, sleeves can
be used to treat a bifurcated treatment site, post-jailing. For
example, a primary body lumen 501 can be treated with an
appropriately sized primary sleeve 500, which is used to span the
length L.sub.1 of the diffuse lesions 502 at treatment site 504.
The bifurcated secondary lumen 511 is effectively cut off. The
guidewire can be proximally withdrawn and rerouted into the
bifurcation, through the already placed primary sleeve 500, and the
secondary lesion site 514 in the bifurcation may be treated with a
second sleeve 520 as shown in FIG. 9B. The sleeve can include a
soft polymer matrix system that is readily breachable with the
guide wire tip to allow bifurcation access.
[0079] A wide variety of therapeutic agents may be used in the
sleeves. A therapeutic agent may be used singly or in combination
with other therapeutic agents. The terms "therapeutic agent",
"pharmaceutically active agent", "pharmaceutically active
material", "pharmaceutically active ingredient", "drug",
"beneficial agent", "bioactive agent" and other related terms may
be used interchangeably herein and include, but are not limited to,
small organic molecules, peptides, oligopeptides, proteins, nucleic
acids, oligonucleotides, genetic therapeutic agents, non-genetic
therapeutic agents, vectors for delivery of genetic therapeutic
agents, cells, and therapeutic agents identified as candidates for
vascular treatment regimens, for example, as agents that reduce or
inhibit restenosis. The term "small organic molecule" refers to an
organic molecule having 50 or fewer carbon atoms, and fewer than
100 non-hydrogen atoms in total. Generally, exemplary therapeutic
agents include, e.g., sirolimus, everolimus, biolimus (e.g.,
biolimus A9), zotarolimus, tacrolimus and paclitaxel. The
therapeutic agent can be amorphous.
[0080] In some embodiments, exemplary non-genetic therapeutic
agents include anti-thrombogenic agents such as heparin, heparin
derivatives, prostaglandin (including micellar prostaglandin E1),
urokinase, and PPack (dextrophenylalanine proline arginine
chloromethylketone); anti-proliferative agents such as enoxaparin
and angiopeptin, monoclonal antibodies capable of blocking smooth
muscle cell proliferation, hirudin, and acetylsalicylic acid;
anti-inflammatory agents such as dexamethasone, rosiglitazone,
prednisolone, corticosterone, budesonide, estrogen, estrodiol,
sulfasalazine, acetylsalicylic acid, mycophenolic acid, and
mesalamine; anti-neoplastic/anti-proliferative/anti-mitotic agents
such as paclitaxel, epothilone, cladribine, 5-fluorouracil,
methotrexate, azathioprine, doxorubicin, daunorubicin,
cyclosporine, mitomycin, cisplatin, vinblastine, vincristine,
epothilones, endostatin, trapidil, halofuginone, and angiostatin;
anti-cancer agents such as antisense inhibitors of c-myc oncogene;
antimicrobial agents such as triclosan, cephalosporins,
aminoglycosides, nitrofurantoin, silver ions, compounds, or salts;
biofilm synthesis inhibitors such as non-steroidal
anti-inflammatory agents and chelating agents such as
thylenediaminetetraacetic acid,
O,O'-bis(2-aminoethyl)ethyleneglycol-N,N,N',N'-tetraacetic acid and
mixtures thereof; antibiotics such as gentamycin, rifampin,
minocyclin, and ciprofloxacin; antibodies including chimeric
antibodies and antibody fragments; anesthetic agents such as
lidocaine, bupivacaine, and ropivacaine; nitric oxide; nitric oxide
(NO) donors such as linsidomine, molsidomine, L-arginine,
NO-carbohydrate adducts, polymeric or oligomeric NO adducts;
anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD
peptide-containing compound, heparin, antithrombin compounds,
platelet receptor antagonists, anti-thrombin antibodies,
anti-platelet receptor antibodies, enoxaparin, hirudin, warfarin
sodium, Dicumarol, aspirin, prostaglandin inhibitors, platelet
aggregation inhibitors such as cilostazol and tick antiplatelet
factors; vascular cell growth promotors such as growth factors,
transcriptional activators, and translational promotors; vascular
cell growth inhibitors such as growth factor inhibitors, growth
factor receptor antagonists, transcriptional repressors,
translational repressors, replication inhibitors, inhibitory
antibodies, antibodies directed against growth factors,
bifunctional molecules consisting of a growth factor and a
cytotoxin, bifunctional molecules consisting of an antibody and a
cytotoxin; cholesterol-lowering agents; vasodilating agents; agents
which interfere with endogenous vascoactive mechanisms; inhibitors
of heat shock proteins such as geldanamycin; angiotensin converting
enzyme (ACE) inhibitors; beta-blockers; .beta.AR kinase (.beta.ARK)
inhibitors; phospholamban inhibitors; proteinbound particle drugs
such as ABRAXANE.TM.; structural protein (e.g., collagen)
cross-link breakers such as alagebrium (ALT-711); and/or any
combination and prodrugs of the above.
[0081] Exemplary biomolecules include peptides, polypeptides and
proteins; oligonucleotides; nucleic acids such as double or single
stranded DNA (including naked and cDNA), RNA, antisense nucleic
acids such as antisense DNA and RNA, small interfering RNA (siRNA),
and ribozymes; genes; carbohydrates; angiogenic factors including
growth factors; cell cycle inhibitors; and anti-restenosis agents.
Nucleic acids may be incorporated into delivery systems such as,
for example, vectors (including viral vectors), plasmids or
liposomes.
[0082] Non-limiting examples of proteins include serca-2 protein,
monocyte chemoattractant proteins (MCP-1) and bone morphogenic
proteins ("BMPs"), such as, for example, BMP-2, BMP-3, BMP-4,
BMP-5, BMP-6 (VGR-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11,
BMP-12, BMP-13, BMP-14, and BMP-15. Preferred BMPs are any of
BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7. These BMPs can be
provided as homodimers, heterodimers, or combinations thereof,
alone or together with other molecules. Alternatively, or in
addition, molecules capable of inducing an upstream or downstream
effect of a BMP can be provided. Such molecules include any of the
"hedgehog" proteins, or the DNAs encoding them. Non-limiting
examples of genes include survival genes that protect against cell
death, such as antiapoptotic Bcl-2 family factors and Akt kinase;
serca 2 gene; and combinations thereof. Non-limiting examples of
angiogenic factors include acidic and basic fibroblast growth
factors, vascular endothelial growth factor, epidermal growth
factor, transforming growth factors .alpha. and .beta.,
platelet-derived endothelial growth factor, platelet-derived growth
factor, tumor necrosis factor .alpha., hepatocyte growth factor,
and insulin-like growth factor. A non-limiting example of a cell
cycle inhibitor is a cathespin D (CD) inhibitor. Non-limiting
examples of anti-restenosis agents include p15, p16, p18, p19, p21,
p2'7, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase
inhibitors and combinations thereof and other agents useful for
interfering with cell proliferation.
[0083] Exemplary small molecules include hormones, nucleotides,
amino acids, sugars, and lipids and compounds having a molecular
weight of less than 100 kD.
[0084] Exemplary cells include stem cells, progenitor cells,
endothelial cells, adult cardiomyocytes, and smooth muscle cells.
Cells can be of human origin (autologous or allogenic) or from an
animal source (xenogenic), or genetically engineered. Non-limiting
examples of cells include side population (SP) cells, lineage
negative (Lin-) cells including Lin-CD34-, Lin-CD34+, Lin-cKit+,
mesenchymal stem cells including mesenchymal stem cells with 5-aza,
cord blood cells, cardiac or other tissue-derived stem cells, whole
bone marrow, bone marrow mononuclear cells, endothelial progenitor
cells, skeletal myoblasts or satellite cells, muscle derived cells,
go cells, endothelial cells, adult cardiomyocytes, fibroblasts,
smooth muscle cells, adult cardiac fibroblasts +5-aza, genetically
modified cells, tissue engineered grafts, MyoD scar fibroblasts,
pacing cells, embryonic stem cell clones, embryonic stem cells,
fetal or neonatal cells, immunologically masked cells, and teratoma
derived cells. Any of the therapeutic agents may be combined to the
extent such combination is biologically compatible.
[0085] Examples of medical devices benefiting from use in
conjunction with the present disclosure vary widely and can include
implantable or insertable medical devices, for example, stents
(including coronary vascular stents, peripheral vascular stents,
cerebral, urethral, ureteral, biliary, tracheal, gastrointestinal
and esophageal stents), stent coverings, stent grafts, vascular
grafts, abdominal aortic aneurysm (AAA) devices (e.g., AAA stents,
AAA grafts), vascular access ports, dialysis ports, catheters
(e.g., urological catheters or vascular catheters such as balloon
catheters and various central venous catheters), guide wires,
balloons, filters (e.g., vena cava filters, mesh filters, and
distal embolic protection devices), embolization devices including
cerebral aneurysm filler coils (including Guglielmi detachable
coils and metal coils), septal defect closure devices, myocardial
plugs, patches, electrical stimulation leads, including leads for
pacemakers, leads for implantable cardioverter-defibrillators,
leads for spinal cord stimulation systems, leads for deep brain
stimulation systems, leads for peripheral nerve stimulation
systems, leads for cochlear implants and leads for retinal
implants, ventricular assist devices including left ventricular
assist hearts and pumps, total artificial hearts, shunts, valves
including heart valves and vascular valves, anastomosis clips and
rings, tissue bulking devices, and tissue engineering scaffolds for
cartilage, bone, skin and other in vivo tissue regeneration,
sutures, suture anchors, tissue staples and ligating clips at
surgical sites, cannulae, metal wire ligatures, urethral slings,
hernia "meshes", artificial ligaments, orthopedic prosthesis such
as bone grafts, bone plates, fins and fusion devices, joint
prostheses, orthopedic fixation devices such as interference screws
in the ankle, knee, and hand areas, tacks for ligament attachment
and meniscal repair, rods and pins for fracture fixation, screws
and plates for craniomaxillofacial repair, dental implants, or
other devices that are implanted or inserted into the body and from
which therapeutic agent is released.
[0086] In some embodiments, suitable medical devices on which a
sleeve may be carried include, but are not limited to, those that
have a tubular or cylindrical like portion. A tubular portion of a
medical device need not be completely cylindrical. The
cross-section of the tubular portion can be any shape, such as
rectangle, a triangle, etc., not just a circle. Such devices
include, but are not limited to, stents, balloons of a balloon
catheters, grafts, and valves (e.g., a percutaneous valve). A
bifurcated stent is also included among the medical devices which
can be fabricated by the methods described herein. The device can
be made of any material, e.g., metallic, polymeric, and/or ceramic
material.
[0087] In some embodiments, examples of balloon materials include
relatively non-complaint materials such as polyamides, for
instance, polyamide homopolymers and copolymers and composite
materials in which a matrix polymer material, such as polyamide, is
combined with a fiber network (e.g., Kevlar.RTM.: an aramid fiber
made by Dupont or Dyneema.RTM., a super-strong polyethylene fiber
made by DSM Geleen, the Netherlands). Specific examples of
polyamides include nylons, such as nylon 6, nylon 4/6, nylon 6/6,
nylon 6/10, nylon 6/12, nylon 11 and nylon 12 and
poly(ether-coamide) copolymers, for instance, polyether-polyamide
block copolymer such as poly(tetramethylene oxide-b-polyamide-12)
block copolymer, available from Elf Atochem as PEBAX. Examples of
balloon materials also include relatively complaint materials such
as silicone, polyurethane or compliant grades of PEBAX having a
larger percentage of poly ether, for example PEBAX 63D. In some
embodiments, examples of balloon materials can include
semi-compliant polymer materials.
Method of Manufacture
[0088] Where the delivery device is a balloon, the sleeves may be
applied to the balloon in a folded state to minimize interactions
between the device and the balloon that would have to be disrupted
for device delivery, thereby improving release. In some
embodiments, sleeves can be made and then applied to a delivery
device. For example, a drug delivery sleeve comprising an inner
release region, a drug-releasing biodegradable fibrous layer, and
an outer adhesive region may be formed and applied to a balloon,
which may be folded in certain embodiments.
[0089] In some embodiments, the balloon is manufactured by
extrusion technology. Referring to FIG. 9A, biodegradable substrate
layer 104 can be formed by spraying or otherwise applying (e.g.,
dipping, brushing, painting) a polymer/therapeutic agent solution
to a cylindrical non-stick template 600 (e.g., a
poly(tetrafluoroethylene) "PTFE" template). Once the biodegradable
substrate layer is formed, the tissue-adhesive region 106 can be
applied to the substrate layer, in a selective manner at predefined
patterns, as illustrated in FIG. 9B. Tissue adhesive region 106 can
be applied, for example, by dipping, spraying, dropping-on-demand,
and/or roll-coating. Upon completion of sleeve formation, the
coating apparatus can be dismantled to leave the sleeve 100, which
can be removed from the PTFE template, as illustrated in FIG. 9C.
The PTFE template can be reused.
[0090] Referring to FIG. 10A, the sleeve 100 can then be introduced
over a carrier balloon 102, which can have pre-applied balloon
release region 108. Referring to FIG. 10B, the sleeve can be fitted
over the device and the carrier balloon can be subsequently
inflated to cause a mechanical interaction between the carrier
balloon and the sleeve, thereby allowing the release layer to be in
contact with the sleeve. Referring to FIG. 10C, deflation can cause
the sleeve to follow the balloon to which it is now adhered to and
to reform the underlying folded shape of the balloon. To form
stacked sleeves, the process is repeated for multiple sleeves with
application of inter-sleeve release region (when present) before
insertion of a balloon into each overlying sleeve.
[0091] In some embodiments, the sleeve includes an elastomeric
material so that it can be placed and folded with a balloon
carrier, such that when expanded in a treatment site, plastic
deformation of the sleeve can be permanently induced. During the
balloon folding process, the sleeve is sized to conform to the
balloon diameter, ensuring that post balloon folding, a reduced
profile is achieved. In some embodiments, no additional
balloon-adhesion region is required.
[0092] In some embodiments, rather than an elastomeric material
that would wrap around and be folded along with the balloon, a tube
of elastomeric material having tissue-adhesive region can be sized
such that it can be placed over a folded balloon. In this case, the
sleeve and the balloon can have a smaller assembly profile, as the
sleeve is not folded together with the balloon. The sleeve can
expand with the unfolding balloon during inflation, which can
induce plastic deformation of the sleeve, and the sleeve can remain
and adhere at the inflated diameter within a treatment site after
removal of the balloon catheter.
[0093] In some embodiments, the balloon cones can be puffed (e.g.,
during packaging and/or device delivery) to ensure securement of
the sleeve.
[0094] Optionally, a stent may be provided (a) before application
of the sleeve (in the event an abluminal sleeve is desired for the
stent) or (b) after application of the sleeve (in the event an
adluminal sleeve is desired for the stent). As another example, a
drug delivery sleeve comprising an inner release region, a first
drug-releasing biodegradable substrate layer, a stent, a second
drug-releasing biodegradable substrate layer, and an outer adhesive
region may be formed and applied to a balloon, which may be folded
in certain embodiments. Different drugs may be supplied in the
biodegradable substrate layers, for example, an endothelial cell
growth promoter may be provided in the inner adlumenal
biodegradable substrate layer and an antirestenotic drug may be
provided in the outer ablumenal biodegradable substrate layer.
[0095] In other embodiments, sleeves may be formed on the surface
of the delivery device. As a specific example (among many other
possibilities), a release region may first be applied to a surface
of an inflatable balloon. A biodegradable polymer containing layer
including a therapeutic agent is then formed over the release
region. In a subsequent step, an adhesive region is provided over
the biodegradable substrate layer. As a more specific example, a
release region may first be applied to a surface of an inflatable
balloon formed from a material such as nylon, polyurethane or
PEBAX, among others. The release region may comprise, among other
possibilities, (a) a shear sensitive adhesive or (b) a zwitterionic
release substance such as phosphorylcholine in combination with
saline microcapsules (unless a micro-porous or weeping balloon is
employed, in which case the saline microcapsules will be excluded).
A biodegradable substrate layer, for example, comprising hyaluronic
acid and paclitaxel as a therapeutic agent is then formed over the
release region, for instance, via a spraying process. The
hyaluronic acid in the biodegradable substrate layer may then be
crosslinked by applying genipin to the fibrous layer. In a
subsequent step, DOPA is applied to the outer fiber layer surface
as an adhesive substance, among other possibilities.
[0096] Optionally, a stent may be provided (a) before application
of the biodegradable substrate layer (in the event an abluminal
biodegradable layer is desired), (b) after application of the
biodegradable substrate layer (in the event a adluminal
biodegradable substrate layer is desired) or (c) after application
of one biodegradable substrate layer, followed by formation of
another biodegradable substrate layer (in the event that a
biodegradable substrate layer-encapsulated stent structure with
adluminal and abluminal biodegradable substrate layers is
desired).
[0097] As noted above, examples of biodegradable substrate layers
include non-porous layers (e.g., hydrogel layers) and porous layers
(e.g., fibrous layers). Non-porous layers may be provided using
techniques such as by dipping, spray coating, coating with an
applicator (e.g., by roller, brush, etc), and so forth.
[0098] Fibrous layers may be formed using, for example, fiber
spinning techniques. For example, electrospinning is a fiber
spinning technique by which a suspended drop of polymer (e.g., a
polymer in a suitable solvent) is charged with tens of thousands of
volts. At a characteristic voltage, the droplet forms a Taylor
cone, and a fine jet of polymer releases from the surface in
response to the tensile forces generated by interaction of an
applied electric field with the electrical charge carried by the
jet. This produces a filament of material. This jet can be directed
to a grounded surface such as a balloon delivery system and
collected as a continuous web of fibers that can be adjusted to
give fibers ranging in size, for example, from 50 nm to 100 nm to
250 nm to 500 nm to 1 micron to 2.5 microns to 5 microns to 10
microns to 20 microns. To ensure good coverage, the balloon
delivery system may be rotated and reciprocated relative to the
jet. Multiple dispensers with differing concentrations of starting
materials may be utilized to produce higher concentrations of
selected materials in specific areas of the nanofibrous network.
Further information on electrospinning may be found, for example,
in US 2005/0187605 to Greenhalgh et al. See also Y. Ji et al.,
"Electrospun three-dimensional hyaluronic acid nanofibrous
scaffolds," Biomaterials 27 (2006) 3782-3792.
[0099] Porous layers including electrospun fibrous layers increase
available surface area and therefore may increase release of any
therapeutic agents and increase biodegradation rate relative to
nonporous layers. Moreover, such layers may serve to create a
scaffold for cell seeding, growth and/or proliferation. For
example, in the case of vascular devices, such layers may serve as
a scaffold for endothelial cell seeding, growth and/or
proliferation in vivo.
[0100] In some embodiments, it may be desirable to roughen a
surface of interest before performing depositions described herein.
For example, a surface may be roughened to provide a series of
nooks or invaginations on/within the surface. Any surface may be
roughened, e.g., a metallic, polymeric or ceramic surface. Surfaces
can be roughened using any technique known in the art. Particularly
useful methods for roughening surfaces, such as the surfaces of a
stent, are described, e.g., in U.S. Ser. No. 12/205,004, which is
hereby incorporated by reference. The surface of a balloon may also
be roughened.
[0101] Further, as will be appreciated by skilled practitioners, a
biodegradable substrate layer can be deposited on an entire surface
of a template or onto only part of a surface of the template. This
can be accomplished using template-shielding masks to shield the
portions on which coatings are not to be deposited. In some
embodiments, the template is a stent. It may be desirable to
deposit only on the abluminal surface of the stent. This
construction may be accomplished by, e.g. coating the stent before
forming the fenestrations. In other embodiments, it may be
desirable to deposit only on abluminal and "cutface" surfaces of
the stent. This construction may be accomplished by, e.g.,
depositing on a stent containing a mandrel, which shields the
luminal surfaces.
[0102] In various embodiments, one or more therapeutic agents may
also be included, for example, along with one or more biodegradable
polymers in a solution that is used to form a biodegradable
substrate layer. As an alternative, a biodegradable polymer and one
or more therapeutic agents may be simultaneously deposited (e.g.,
from separate containers) to form a biodegradable substrate layer.
As another alternative, one or more therapeutic agents may be
applied (e.g., in solution) to the biodegradable substrate layer
after it is formed.
EXAMPLES
Example 1
[0103] A sleeve includes PLGA/Everolimus in a 50:50 composition.
The design has a nominal dosage of 1 .mu.g/mm.sup.2 Everolimus.
This sleeve has a tissue adherent layer including a
poly(N-isopropylacrylamide) gel matrix and a balloon adherent layer
including iopromide. The tissue adhesive region is applied by
spraying. The balloon adhesive regions are applied by spraying.
Example 2
[0104] A stacked cuff device includes an inner tubular assembly
that includes a sleeve having PLGA/Everolimus in a 50:50
composition. The design has a nominal dosage of 1 .mu.g/mm.sup.2
Everolimus. An outer tubular assembly includes a sleeve having
PLGA/Everolimus in a 50:50 composition. This sleeve has a tissue
adherent layer including a poly(N-isopropylacrylamide) gel matrix
and a balloon adherent layer including a gelatin-based adhesive.
The tissue adhesive region is applied by spraying. The
balloon/sleeve adhesive regions are applied by spraying.
Example 3
[0105] A stacked cuff device includes an inner tubular assembly
that includes a sleeve having PLA/Paclitaxel in a 90:10
composition. The inner tubular sleeve assembly has a nominal dosage
of approximately 1 .mu.g/mm.sup.2 Paclitaxel. An outer tubular
assembly includes a sleeve having PLA/Paclitaxel in a 90:10
composition. The outer tubular sleeve assembly has a nominal dosage
of approximately 1 .mu.g/mm.sup.2 paclitaxel. This sleeve has a
tissue adherent layer including a poly(N-isopropylacrylamide) gel
matrix and a balloon adherent layer including a gelatin hydrogel
glue. The tissue adhesive region is applied by drop-on-demand
technology. The balloon/sleeve adhesive regions are applied by
drop-on-demand technology.
[0106] All references, such as patent applications, publications,
and patents, referred to herein are incorporated by reference in
their entirety.
[0107] A number of embodiments of the disclosure have been
described. Nevertheless, it will be understood that various
modifications may be made without departing from the spirit and
scope of the disclosure. Accordingly, other embodiments are within
the scope of the following claims.
* * * * *